Adv. mediated by IgG Fc-Fc receptor interactions following antibody-mediated opsonophagocytosis of bacteria. Antibody-based therapies, when coupled with immune modulators, such as P4 peptide, may be an effective tool together with antibiotics in our armamentarium against severe pneumonia. INTRODUCTION Secondary bacterial pneumonia is usually a common complicating factor that contributes to the morbidity and mortality associated with epidemic and pandemic influenza (15). During the 1918 Spanish flu pandemic, 95% of fatal cases characterized by autopsy were associated with a bacterial etiology (18). Furthermore, in the recent H1N1 pandemic, examination of fatal and severe pneumonias identified a secondary bacterial pathogen in 25 to 56% 17 alpha-propionate of cases, with (group A streptococcus) identified as prominent superinfecting brokers (1, 5, 6, 13, 18, 20, 24). Secondary bacterial pneumonia as a complication of influenza is usually difficult to treat. Despite the use of appropriate antibiotic regimens in 95 to 99% of severe cases of bacterial superinfection during pandemic H1N1 influenza computer virus in 2009 2009, a high mortality rate (14 to 46%) was observed. This suggests an inefficiency of antibiotic therapies for bacterial superinfections (4, 5, 7, 10, 20). Recent data from a murine model suggest that treatment of postinfluenza bacterial pneumonia with cell wall-active, -lactam antibiotics exaggerates the inflammatory response to bacteria in the lung and therapies that do not cause lysis of Gram-positive pathogens may be a better alternate (8, 9, 12). Mouse monoclonal to CD68. The CD68 antigen is a 37kD transmembrane protein that is posttranslationally glycosylated to give a protein of 87115kD. CD68 is specifically expressed by tissue macrophages, Langerhans cells and at low levels by dendritic cells. It could play a role in phagocytic activities of tissue macrophages, both in intracellular lysosomal metabolism and extracellular cellcell and cellpathogen interactions. It binds to tissue and organspecific lectins or selectins, allowing homing of macrophage subsets to particular sites. Rapid recirculation of CD68 from endosomes and lysosomes to the plasma membrane may allow macrophages to crawl over selectin bearing substrates or other cells. 17 alpha-propionate However, as these pathogens continue to acquire resistance, alternatives to antibiotics or adjunctive therapies may be required for effective remedy. As early as 1891, patients with life-threatening bacterial pneumonia were treated with pathogen-specific immune sera derived from rabbits or horses, with drastic reductions in morbidity and mortality (3). In the preantibiotic era, passive immunotherapy was the primary mode of treatment for many infectious diseases, including diphtheria, tetanus, and scarlet fever (2). However, several factors impeded its continued use in the modern era, including toxicity and serum sickness, which occurred in 10 to 50% of patients. In 1937, the introduction of sulfonamides active against common brokers of community-acquired pneumonia halted the common use of passive immunotherapy. Currently, antibody therapy is usually indicated as a treatment in only a few, select situations, such as for toxin neutralization (diphtheria, tetanus, and botulism) or for postexposure prophylaxis of viral infections (rabies, measles, hepatitis A and B, and Ebola viruses). However, several recent improvements in antibody harvesting and monoclonal antibody production are prompting reconsideration of passive immunotherapy. Several recent studies have sought to improve upon passive immunotherapy regimens for main pneumococcal pneumonia through the use of an immunomodulatory peptide as adjunctive therapy for intravenous (i.v.) immune globulin (IVIG) (17, 23). P4 is usually a 28-amino-acid peptide derived from pneumococcal surface adhesin A (22). It has been used to successfully treat 17 alpha-propionate mice with normally fatal infections (23). This peptide has been found to increase the adherence and internalization of pneumococci and to activate host immune cells (22, 23). In this study, we sought to determine whether combined therapy with P4 and IVIG could be used to treat mice with severe secondary bacterial pneumonia following influenza. We hypothesized that this combined therapy of IVIG and P4 peptide would facilitate innate immune responses and reduce the 17 alpha-propionate pneumococcal burden following influenza contamination, which stimulates bacterial overgrowth. We statement that this regimen rescues mice from severe influenza-pneumococcal coinfections, suggesting that it may serve as a viable alternate or adjunct to antibiotic therapy. MATERIALS AND METHODS Mice. Six- to eight-week-old female BALB/c mice (Jackson Laboratory, Bar Harbor, ME) were managed in a biosafety level 2 facility in the Animal Resource Center at St. Jude Children’s Research Hospital (SJCRH). All experimental procedures were approved by the Animal Care and Use Committee.